High mobility group box 1 (HMGB1)
The HMGB1 protein is a pro-inflammatory cytokine with pro-inflammatory properties that acts as an initiator of neuroinflammation. It has been associated with traumatic brain injury (TBI) and acute brain injury (EBI) in the aftermath of a subarachnoid hemorrhage (SAH) (Paudel, Angelopoulou, Piperi, Othman & Shaikh, 2020). After SAH, HMGB1 expression rises, and it plays a role in the disease’s development (Murakami, Koide, Dumont, Russell, Tranmer & Wellman, 2011). The activation of Janus kinases 2 (JAK2)/Signal transducer and activator of transcription by HMGB1 causes SAH-induced EBI (STAT3). In nuclei, HMGB1 is involved in chromatin structure preservation, transcription activity modulation, and DNA repair. HMGB1, on the other hand, is considered a typical damage-associated molecular pattern (DAMP) since it is translocated and released extracellularly from a range of brain cells, including neurons and microglia, and hence contributes to the pathophysiology of many CNS diseases (Nishibori, Wang, Ousaka & Wake, 2020). HMGB1 has been demonstrated to promote inflammatory cascades by binding to TLR4/TLR2 and RAGE, leading in activation of NF-κB, IL-6, IL-8, TNF-, MyD88, iNOS, ERK1 and ERK2 (Park et al., 2003). Extracellular HMGB1 release could play a key role in activating the early inflammatory responses by stimulating numerous receptors, resulting in BBB breakdown (Nishibori, Wang, Ousaka & Wake, 2020). HMGB1 induced vascular smooth muscle cells (VSMCs) and regulated VSMC phenotypic transition during SAH via interacting with IFN-γ (Wang, Zhang, Liang, Wu, Zhong & Sun, 2019). After treatment with anti-HMGB1 mAb, the vascular remodeling and VSMC phenotypic shift found in SAH were reported to be reduced, principally by reversing SAH-induced up-regulation of HMGB1, microglial activation, and brain edema. HMGB1 was once assumed to be a negative cytokine, but it has now been revealed to enhance the inflammatory response in acute stroke patients. On day 14 following SAH, however, (Tian et al., 2017) found that HMGB1 expression was considerably higher than in the sham group. This finding suggested that HMGB1 may play a role in the healing of brain injury following SAH. The pro- and anti-inflammatory effects of HMGB1 demonstrate the protein’s complexity and role in circumstances following SAH, implying that more research is needed to validate its involvement in occurrences like EBI.